Mechanisms of resistance to immune checkpoint inhibitors

Area of Science:

• Immunology
• Oncology
• Cancer Therapy

Background:

• Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1/PD-L1 have transformed cancer treatment by enhancing anti-tumour immune responses.
• Unlike conventional therapies, ICIs disrupt T-cell signaling, leading to durable responses and immunological memory in some patients.
• Resistance to ICIs, both primary and acquired, is a significant clinical challenge, with limited biomarkers for prediction.

Purpose of the Study:

• To review emerging clinical and pre-clinical data on mechanisms of innate and acquired resistance to immune checkpoint inhibitors.
• To highlight the need for improved understanding of ICI resistance to identify predictive biomarkers and guide therapeutic strategies.
• To explore how understanding resistance can inform optimal combination and sequencing of ICI therapies.

Main Methods:

• Review of existing clinical trial data and pre-clinical studies investigating immune checkpoint inhibitor response and resistance.
• Analysis of correlative clinical data to infer mechanisms of resistance.
• Synthesis of current knowledge on molecular and immunologic factors influencing ICI efficacy.

Main Results:

• While ICIs induce durable responses in some patients, a significant proportion exhibit primary resistance.
• Late relapses suggest the emergence of acquired resistance, even after initial response.
• Robust biomarkers for predicting ICI response or resistance remain largely elusive.

Conclusions:

• Understanding the molecular and immunological mechanisms of ICI resistance is critical for clinical advancement.
• Identifying novel biomarkers could predict patient response and guide personalized treatment strategies.
• Further research into resistance mechanisms will inform the development of more effective combination and sequencing therapies involving ICIs.